Connections between starvation and immunological memory

Focus on autophagy's functions in memory T cells

Effects of cocaine exposure in adolescent rodents

The effects on neurons are like losing entire branches from a tree, neuroscientists are finding

Frailty: we know it when we can measure it

Look beyond the cane. Emory researchers are seeking to define and measure frailty, to aid in surgery-related decision-making.

Cancer

No junk: long RNA mimics DNA, restrains hormone responses

It arises from what scientists previously described as “junk DNA” or “the dark matter of the genome,” but this gene is definitely not junk. The gene Gas5 acts as a brake on steroid hormone receptors, making it a key player in diseases such as hormone-sensitive prostate and breast cancer.

Unlike many genes scientists are familiar with, Gas5 does not encode a protein. It gets transcribed into RNA, like many other genes, but with Gas5 the RNA is what’s important, not the protein. The RNA accumulates in cells subjected to stress and soaks up steroid hormone receptors, preventing them from binding DNA and turning genes on and off.

Emory researchers have obtained a detailed picture of how the Gas5 RNA interacts with steroid hormone receptors. Their findings show how the Gas5 RNA takes the place of DNA, and give hints as to how it evolved.

The results were published Friday in Nature Communications.

Scientists used to think that much of the genome was “fly-over country”: not encoding any protein and not even accessed much by the cell’s gene-reading machinery. Recent studies have revealed that a large part of the genome is copied into lincRNAs (long intergenic noncoding RNAs), of which Gas5 is an example. Read more

Posted on by Quinn Eastman in Cancer, Immunology Leave a comment

Rules of thumb for drug discovery

People interested in drug discovery may have heard of “Lipinski’s rule of five,” a rough-and-ready set of rules for determining whether a chemical structure is going to be viable as a orally administered drug or not. They basically say that if a compound is too big, too greasy or too complicated, it’s not going to get into the body and make it to the cells you want to affect. These guidelines have been the topic of much debate among medicinal chemists and pharmacologists.

The namesake for this set of rules, Chris Lipinski, will be speaking at Winship Cancer Institute Wednesday afternoon (4:30 pm, Nov 5, C5012) on “The Rule of 5, Public Chemistry-Biology Databases and Their Impact on Chemical Biology and Drug Discovery.” Lipinski spent most of his career at Pfizer (while there, he published the “rule of 5 paper“) and now is a consultant at Melior Discovery.

Posted on by Quinn Eastman in Cancer, Uncategorized Leave a comment

Divide and conquer vs lung cancer

Doctors are using a “divide and conquer” strategy against lung cancer, and in some corners of the battlefield, it’s working. A few mutations – genetic alterations in the tumor that don’t come from the patient’s normal cells — have been found for which drugs are effective in pushing back against the cancer.

However, most lung tumors do not have one of these mutations, and response rates to conventional chemotherapy in patients with advanced lung cancer are poor. Generally, only around 20 percent of patients show a clinical response, in that the cancer retreats noticeably for some time.

Johann Brandes and colleagues at Winship Cancer Institute have been looking for biomarkers that can predict whether an advanced lung tumor is going to respond to one of the most common chemotherapy drug combinations, carboplatin and taxol.

“The availability of a predictive test is desirable since it would allow patients who are unlikely to benefit from this treatment combination to be spared from side effects and to be selected for other, possibly more effective treatments,” Brandes says.

Brandes’ team’s data comes from looking at patients with advanced lung cancer at the Atlanta VAMC from 1999 to 2010. In a 2013 paper in Clinical Cancer Research, the team looked at a protein called CHFR. It controls whether cells can reign in their cycles of cell division while being bombarded with chemotherapy.

In this group being treated with carboplatin and taxol, patients who had tumors that measured low in this protein lived almost four months longer, on average, than those who had tumors that were high (9.9 vs 6.2 months).

His team takes a similar approach in a new paper published in PLOS One. Postdoc Seth Brodie is the first author of the PLOS One paper; he is also co-first author of the CHFR paper along with Rathi Pillai. Read more

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Pilot human trial for image-guided cancer surgery tool

The Spectropen, a hand-held device developed by Emory and Georgia Tech scientists, was designed to help surgeons see the margins of tumors during surgery.

Some of the first results from procedures undertaken with the aid of the Spectropen in human cancer patients were recently published by the journal PLOS One. A related paper discussing image-guided removal of pulmonary nodules was just published in Annals of Thoracic Surgery.

To test the Spectropen, biomedical engineer Shuming Nie and his colleagues have been collaborating with thoracic surgeon Sunil Singhal at the University of Pennsylvania.

As described in the PLOS One paper, five patients with cancer in their lungs or chest participated in a pilot study at Penn. They received an injection of the fluorescent dye indocyanine green (ICG) before surgery.

ICG is already FDA-approved for in vivo diagnostics and now used to assess cardiac and liver function. ICG accumulates in tumors more than normal tissue because tumors have leaky blood vessels and membranes. The Spectropen shines light close to the infrared range on the tumor, causing it to glow because of the fluorescent dye.

[This technique resembles the 5-aminolevulinic acid imaging technique for brain tumor surgery being tested by Costas Hadjipanayis, described in Emory Medicine.]

In one case from the PLOS One article, the imaging procedure had some tangible benefits, allowing the surgeons to detect the spread of cancerous cells when other modes of imaging did not. Read more

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Potential anticancer drugs from humble sources

Jing Chen and colleagues at Winship Cancer Institute recently published a paper in Molecular CellMost of the paper deals with a metabolic enzyme, 6PGD (6-phosphogluconate dehydrogenase), and how it is more active in cancer cells.

Rhubarb_Flower

Rheum palmatum/Chinese rhubarb/da-huang

Tucked in at the end is a note that an inhibitor of 6GPD with an odd name, physcion, has anticancer activity in Chen’s team’s hands. Physcion, also known as parietin, is an orange-yellow pigment extractable from lichens and Chinese rhubarb that has been employed as an anti-mildew agent.

Probing cancer cells’ warped metabolism is a promising approach, for both drug discovery and finding effective ways to combine existing drugs, because of the Warburg effect: cancer cells’ tendency to suck up lots of sugar and use it in energy-inefficient ways. Read more

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Cancer immunotherapy, meet chimera

697px-Chimera_d'arezzo,_fi,_03

In Greek mythology, the chimera was a monstrous fire-breathing creature composed of the parts of three animals: a lion, a snake and a goat.

Adoptive cell transfer is advancing as a cancer immunotherapy technique. It involves removing some of a patient’s immune cells, culturing them in the laboratory, and then infusing the cells back into the patient. The idea is to enhance the ability of the immune cells to attack the tumors far beyond what the immune system was able of doing on its own.

Two promising examples are the National Cancer Institute’s approach of treating advanced melanoma with IL-2-stimulated immune cells, and several investigators’ approach of genetically engineering T cells to attack leukemias or lymphomas.

Jacques Galipeau and colleagues at Winship Cancer Institute have developed a chimeric molecule for stimulating immune cells, which appears to have unique powers beyond simply the sum of its two parts. The molecule is called GIFT4, a fusion of the immune signaling molecules GM-CSF (often used in cancer treatment) and IL-4.

Read more

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Statins, prostate cancer and mitochondria

In honor of Fathers’ Day, we are examining a connection between two older-male-centric topics: statins and prostate cancer.

Statins are a very widely prescribed class of drugs used to lower cholesterol levels, for the purpose of preventing cardiovascular disease. In cell culture, they appear to kill prostate cancer cells, but the epidemiological evidence is murkier. Statin effects on prostate cancer incidence have been up in the air, but recent reports point to the possibility that starting statins may slow progression, after a man has been diagnosed with prostate cancer.

Winship Cancer Institute researchers have some new results that shed some light on this effect. John Petros, Rebecca Arnold and Qian Sun have found that mutations in mitochondrial DNA make prostate cancer cells resistant to cell death induced by simvastatin [Zocor, the most potent generic statin]. Sun recently presented the results at the American Urological Association meeting in Orlando.

In other forms of cancer such as breast and lung cancer, genomic profiling can determine what DNA mutations are driving cancer growth and what drugs are likely to be effective in fighting the cancer. The prostate cancer field has not reached the same point, partly because prostate cancers are not generally treated with chemotherapy until late in the game, Petros says. But potentially, information on mitochondrial mutations could guide decisions on whether to initiate statin (or another) therapy.

“This is part of our soapbox,” he says. “When we are looking at mutational effects on prostate cancer, let’s be sure to include the mitochondrial genome.”

Winship’s Carlos Moreno and his colleagues are working on the related question of biomarkers that predict prostate cancer progression, after prostatectomy surgery and potentially after just a biopsy.

Read more

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Progesterone could become tool vs glioblastoma

The hormone progesterone could become part of therapy against the most aggressive form of brain cancer. High concentrations of progesterone kill glioblastoma cells and inhibit tumor growth when the tumors are implanted in mice, researchers have found.

The results were recently published in the Journal of Steroid Biochemistry and Molecular Biology.

Glioblastoma is the most common and the most aggressive form of brain cancer in adults, with average survival after diagnosis of around 15 months. Surgery, radiation and chemotherapy do prolong survival by several months, but targeted therapies, which have been effective with other forms of cancer, have not lengthened survival in patients fighting glioblastoma.

The lead author of the current paper is assistant professor of emergency medicine Fahim Atif, PhD. The findings with glioblastoma came out of Emory researchers’ work on progesterone as therapy for traumatic brain injury and more recently, stroke. Atif, Donald Stein and their colleagues have been studying progesterone for the treatment of traumatic brain injury for more than two decades, prompted by Stein’s initial observation that females recover from brain injury more readily than males. There is a similar tilt in glioblastoma as well: primary glioblastoma develops three times more frequently in males compared to females.

These results could pave the way for the use of progesterone against glioblastoma in a human clinical trial, perhaps in combination with standard-of-care therapeutic agents such as temozolomide. However, Stein says that more experiments are necessary with grafts of human tumor cells into animal brains first. His team identified a factor that may be important for clinical trial design: progesterone was not toxic to all glioblastoma cell lines, and its toxicity may depend on whether the tumor suppressor gene p53 is mutated.

Atif, Stein, and colleague Seema Yousuf found that low, physiological doses of progesterone stimulate the growth of glioblastoma tumor cells, but higher doses kill the tumor cells while remaining nontoxic for healthy cells. Similar effects have been seen with the progesterone antagonist RU486, but the authors cite evidence that progesterone is less toxic to healthy cells. Progesterone has also been found to inhibit growth of neuroblastoma cells (neuroblastoma is the most common cancer in infants), as well as breast, ovarian and colon cancers in cell culture and animal models.

 

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Fine tuning an old-school chemotherapy drug

First approved by the FDA in the 1970s, the chemotherapy drug cisplatin and its relative carboplatin remain mainstays of treatment for lung, head and neck, testicular and ovarian cancer. However, cisplatin’s use is limited by its toxicity to the kidneys, ears and sensory nerves.

Paul Doetsch’s lab at Winship Cancer Institute has made some surprising discoveries about how cisplatin kills cells. By combining cisplatin with drugs that force cells to rely more on mitochondria, it may be possible to target it more specifically to cancer cells and/or reduce its toxicity.

Cisplatin emerged from a serendipitous discovery in the 1960s by a biophysicist examining the effects of electrical current on bacterial cell division. It wasn’t the current that stopped the bacteria from dividing – it was the platinum in the electrodes. According to Siddhartha Mukherjee’s book The Emperor of All Maladies, cisplatin became known as “cisflatten” in the 1970s and 1980s because of its nausea-inducing side effects.

Cisplatin is an old-school chemotherapy drug, in the sense that it’s a DNA-damaging agent with a simple structure. It doesn’t target cancer cells in some special way, it just grabs DNA with its metallic arms and holds on, forming crosslinks between DNA strands.

But how cisplatin kills cells is more complicated. Along with the direct effects of DNA damage, cisplatin unleashes a storm of reactive oxygen species.

“We wanted to know whether the reactive oxygen species induced by cisplatin had a driving role in cell death or was more of a byproduct,” says postdoc Rossella Marullo, who is the first author of a recent paper with Doestch in PLOS One.

One possible analogy: after the 1906 San Francisco earthquake, the fires were even more destructive than the initial shaking. When asked whether to think of the reactive oxygen species production triggered by cisplatin in the same way as the fires, Doetsch and Marullo say they wouldn’t go that far.

Still, they have uncovered a critical role for mitochondria, cells’ mini-power plants, in cisplatin cell toxicity. The researchers found that mitochondria are the source of cisplatin-induced reactive oxygen species in lung cancer cells. Cancer cell lines that lack functional mitochondria* are less sensitive to cisplatin, and cisplatin’s damage to the mitochondria may be even more important than the damage to DNA in the nucleus, the authors write. However, mitochondrial damage is not important for cisplatin’s less potent [but less toxic] cousin carboplatin.

Cancer cells tend to have a warped metabolism that makes them turn off their mitochondria. This is part of the “Warburg effect” (experts in this area: Winship’s Jing Chen and Malathy Shanmugam). Cancer cells have an increased uptake of sugar, but don’t break it down completely, and use the byproducts as building materials.

What if we could force cancer cells to rely on their mitochondria again, and at the same time, by giving them cisplatin, make that painful for them? This would make cisplatin even more toxic to cancer cells in particular.

The drug DCA (dichloroacetate), which can stimulate cancer cells to use their mitochondria, can also increase the toxicity of cisplatin, at least in cancer cell lines in the laboratory, Marullo and her colleagues show.

Doetsch and radiation oncologist Jonathan Beitler are in the process of planning a clinical trial combining DCA with cisplatin for HPV (human papillomavirus)-positive head and neck cancer. The trial would test whether it might be possible to use a lower dose of cisplatin, reducing toxicity, by combining it with DCA.

“We’ve relied on cisplatin’s efficacy for decades, without fully understanding the mechanism,” Beitler says. “With this new knowledge, it may be possible to manipulate cisplatin’s action so it is more effective and less toxic.”

The applicability of cisplatin and mitochondrial tuning may depend both on cancer cell type and metabolic state, Doetsch adds.

*Cell lines that lack mitochondrial DNA can be obtained by “pickling” them in ethidium bromide, a DNA intercalation agent.

 

 

 

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Moreno: how Big Pharma is slowing cancer research

Winship Cancer Institute’s Carlos Moreno has a sharply written commentary on Reuters, whipping Big Pharma for footdragging on cancer drug discovery for patent/IP-related reasons. Check it out.

Read more

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